17-alkenyl-6{62 -azido-4,5{60 -epoxymorphinan-3-ols

ABSTRACT

The present invention relates to novel 17-alkenyl-6 Beta -azido4,5 Alpha -epoxymorphinan-3-ols having the following structural formula:   IN WHICH R1 is alkenyl such as, for example, allyl. These compounds are useful as analgesics.

United States Patent 1 nu 3,882,127

Meltzer May 6, 1975 [5 17-ALKENYL-6B-AZlDO-4,Sa:-EPOXYMOR- [57] ABSTRACTPHINAN'3OLS The present invention relates to novel l7-alkenyl-6fi- [75]Inventor: Robert I. Meltzer, Rockaway, NJ. P Y P having the followingstructural formula: [73] Assignee: Warner-Lambert Company, MorrisPlains, NJ. H0 22 Filed: Aug. 31, 1913 [2]] Appl. N0.: 393,379 f a 52us. Cl. 260/285; 424/260 2 1\ 51 Int. Cl con 43/28 0 10 [58] Field ofSearch 260/285 3 9 [56] References Cited UNITED STATES PATENTS 3,318,8855/1967 Brown et al. 260/285 OTHER PUBLICATIONS Bognar et 211., ChemicalAbstracts, Vol. 71, 13243x,

1969. Bognar et al., Chemical Abstracts VoL 71, 35l5y, in which R isalkenyl such as, for example, ally]. 1969. These compounds are useful asanalgesics.

Primary Examiner-Donald G. Daus 2 Claims No Drawings AssistantExaminer-Mary C. Vaughn Attorney. Agent, or Firm-Albert H. Graddis;Frank S. Chow l7-ALKENYL-6B-AZIDO-4,5a-EPOXYMORPHI- NAN-3-OLS Thepresent invention relates to novel morphine derivatives and. moreparticularly. the present invention relates tol7-alkenyl-6B-azido-4.5a-epoxymorphinan- 3-ols having the followingstructural formula:

wherein R is alkenyl having 3-8 carbon atoms. e.g.. allyl.

The present invention also includes within its scope pharmaceuticallyacceptable acid addition salts of these novel azidomorphine derivatives.

The compounds of this invention are useful as analgesics andantitussives. They are administered parenterally or orally for themanagement of pain in any of the usual pharmaceutical forms includingtablets, capsules. powders, suspensions, solutions, syrups and the like.Particularly valuable formulations include sus tained releasepreparations which may be compounded by any of the known procedures.Generally these compounds are effective in effecting analgesia at adosage of from about 0.1 to about 0.5 mg. per kg. of body weight. Aswith any analgesic agent, the dosage should be adjusted to the severityof the indication and the degree of response. Moreover the dose may berepeated as appropriate depending upon the nature ofthe particularformulation. the response and the condition of the patient.

According to the present invention the above compounds are prepared byacylating l7-R,-4,5a-epoxymorphinan-3.6a-diol. The acylated product istreated with tosylchloride to give the corresponding 60:-tosyloxymorphinan derivative. Treatment of the tosyl derivative withsodium azide yields the desired compounds of this invention.

The starting compound is disclosed in US. Pat. No. 2,74l.6l 2.

In order to further illustrate the practice of this invention. thefollowing examples are included:

EXAMPLE l Preparation of 3-Acetoxyl7-allyl-4,Sa-epoxymorphinan-6a-ol To7.4 g of l7-allyl-4,5a-epoxymorphinan-3.6a-diol in I200 ml water isadded 120 g of sodium bicarbonate followed by four successive additionsof IS ml of acetic anhydride. After 30 minutes. the mixture is extractedwith four 500 ml portions of chloroform. The combined extracts aredried, filtered and evaporated to give 9.0 g of oil.

EXAMPLE 2 Preparation of 3-Acetoxyl7-allyl-4,5a-epoxy-a-tosyloxymorphinan To a solution of 8.7 g of3-acetoxy-l 7-allyl-4.5aepoxymorphinan-fia-ol in 40 ml pyridine is addeddropwise a solution of 7.5 g tosyl chloride in 40 ml pyridine overminutes maintaining a temperature of 5C. After I hour at 0C and I6 hoursat C the bulk of pyridine is removed under vacuum. Then 400 ml of 5percent sodium bicarbonate is added and the mixture extracted with three500 ml portions of ether. The combined extracts are washed. dried.filtered and evaporated. The residue is dissolved in 20 ml ethanol and4.4. g of tartaric acid in 20 ml ethanol are added. The tartrate isprecipitated by adding benzene. filtered. redissolved in a minimum ofethanol and reprecipitated with petroleum ether to 8.8 g. This isstirred in ml hot water. filtered hot and the cake washed with ethanol,tetrahydrofuran and petroleum ether to give 4.7 g, mp l l ll l4C. Theelemental assay conforms to a dihydrate of the tartrate salt of theabove compound.

Calcd. for CagHgnNOmS .2H20I C. H N,

2.01; S. 4.61. Found: C, 55.05; H. 5.75; N. 2.02; S. 4.5l.

EXAMPLE 3 Preparation of l7-Allyl-6B-azido-4.5a-epoxymorphinan-3-ol Thefree base from 4.5 g of 3-acetoxy-l7-allyl-4.5aepoxy-6wtosyloxymorphinantartrate dihydrate is isolated by treating with aqueous ammoniaextracting into chloroform and evaporating to a residual oil. Thisresidue is heated 24 hours at C with 108 ml dimethylformamide, 6.8 g ofsodium azide and I6 ml of water. The mixture is cooled, poured intowater and extracted into ether. The ether extracts are washed withwater. dried over sodium sulfate and evaporated. The residue isrecrystallized from ether to give 600 mg, mp l33C. The infrared shows astrong band at 2090 cm. [01

l7|.0 (C=1 in MeOH).

Calcd. for C H N O C, 67.43; H. 6.55; N. l6.56. Found: C. 67.20; H.6.716.71 N, 16.65.

I claim:

1. A compound of the formula:

wherein R, is alkenyl having 3 to 8 carbon atoms and thepharmaceutically acceptable acid addition salts.

2. A compound according to claim 1 wherein said alkenyl is allyl.

1. A COMPOUND OF THE FORMULA:
 2. A compound according to claim 1 whereinsaid alkenyl is allyl.